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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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December 15, 2010

Chiral What? Chiral How?

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Posted by Derek

Thanks to an email from a reader, I can bring you this very weird paper from Tetrahedron. The authors claim to have extracted a local plant and isolated nevirapine, (sold as Viramune by Boehringer Ingleheim as a reverse transcriptase inhibitor for HIV).
nevirapine.png
That's kind of odd. I'm no natural products expert, but I've sure seen a lot of them over the years, and that framework (and the N-cyclopropyl) don't look so likely to me. But hey, plants do odd things. That's not what's really puzzling about this paper. No, what's had me staring at it this morning is the claim that, in contrast to the marketed drug, this stuff is optically active nevirapine.

Say what? Try as I might, I can't see any plausible way that that's a chiral compound. The authors seem to think it is, though. They claim optical rotation, somehow, and then say that "The detailed structure and stereochemistry of compound 1 was established unambiguously by single crystal X-ray crystallography." But hold on - that's not as easy as it sounds. Getting absolute configurations from the X-ray data of light-atom-only molecules takes special efforts, and I don't see any being taken (molybdenum X-rays, direct methods, no talk of anomalous dispersion, etc.)

I'm just not willing to see that nitrogen atom as a source of chirality - if it were, shouldn't that be the focus of this whole paper? Instead, the authors just blithely tell us how neat it is that they've isolated the chiral material. In fact, they find it so neat that they tell us two times in a row:

This is a very interesting discovery that naturally occurring optically active nevirapine has been biosynthesized in the seeds of C.viscosa and the optically inactive nevirapine was designed as a selective non-nucleoside inhibitor of HIV-1 reverse transcriptase. It is also a remarkable finding that the seed of C.viscosa is the source of optically active nevirapine, which was also designed and synthesized before its isolation from natural source.

This sounds like some sort of lunatic patent-busting exercise, to be honest. And it sounds as if someone doesn't know what a chiral compound is. And that whoever reviewed this for Tetrahedron was incompetent. And that the editor who let it through should be a least a little bit ashamed. Well?

Comments (73) + TrackBacks (0) | Category: Infectious Diseases | Natural Products | The Scientific Literature


COMMENTS

1. jw on December 15, 2010 9:52 AM writes...

I dont really know what to say, Some nitrogens appear to be chiral as they prefer to be in one state over another, but I cant see even that being the case here

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2. capek on December 15, 2010 9:59 AM writes...

I'm looking at this as a possible anilide atropisomer. I'm still looking...

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3. Anonymous on December 15, 2010 10:11 AM writes...

any possiblity that the two pyridyl nitrogens are being coordinated by a metal ion?

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4. processchemist on December 15, 2010 10:23 AM writes...

I vote for the patent bursting attempt hypothesis. And this is not the first time that we see papers aimed in this direction.
Sales of Viramune are not disclosed by Boheringer, patent expires in 2012 but Cipla, Daiichi Sankyo's India and Ranbaxy have the generic already on the market. The usual mess, just another fancy asymmetry of the current system.

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5. petros on December 15, 2010 10:23 AM writes...

Hmmm

Atropisomerisem looks questionable but the reported rotaion (7.8 at 0.011) is pretty small.

And the mp is only 4 degrees different (lower) from that reported for nevaripine. Prehaps somone will check that the NMR is right

It's also a very odd natural product as you say.

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6. Stiv on December 15, 2010 10:24 AM writes...

it's weird that the cyclopropyl methylenes (and their associated carbons) have different shifts - should be free rotation around the C-N bond.

also, in Fig. 2 (the ORTEP-diagram), what is that thing behind molecule 1? ethyl acetate in the crystal?

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7. petros on December 15, 2010 10:31 AM writes...

Actually picking up on Stiv's poiint (#6). Would be regiosomer of nevaripine, with the methyl proximal to the cyclopropyl substituent be sufficient to give hindered rotation and chirality?

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8. Tex on December 15, 2010 10:53 AM writes...

Ok, we're all forgetting here that chirality and the ability to resolve enantiomers are two different things. If this molecule is not planar (as the X-ray indicates), then there are non-superimposable mirror images and therefore the molecule is chiral. However, if enantiomers can interconvert by a conformational exchange - it then depends on the barrier to inversion. In this case, I do not see immediately what would lead to a large barrier for interconversion. For molecules with chirality at trivalent nitrogen to be configurationally stable and thus resolvable (cf comment 1), this typically means being in a small ring (aziridines) or being bonded to oxygen (oxaziridines, N-alkoxyamines) in order to increase the N-inversion barriers.

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9. Industry Guy on December 15, 2010 10:54 AM writes...

Come on! The paper is from India....enough said. Add it to the pile of chemistry crap coming from there.

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10. Capek on December 15, 2010 10:58 AM writes...

Doesn't the space group of P-1 kind of give it away? It can't be stereochemically pure. With a z value of 2, the other molecule in the unit cell must be the mirror image.

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11. bgg on December 15, 2010 11:02 AM writes...

Perhaps the stabilizing forces involved in the crystal packing provide a sufficient barrier to inversion at N. Chiral crystals are known to form from achiral molecules.

But as for the paper, I don't really believe any of the conclusions.

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12. barry on December 15, 2010 11:15 AM writes...

The central ring would be anti-aromatic (4n) if it were planar. That seems to present the barrier to interconversion between one buckled form and the other. If so, that makes it one of the odd cases where chirality isn't atom-centered, but it wouldn't be unique.

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13. p on December 15, 2010 11:17 AM writes...

I'm away from my work computer and office so don't have access to the paper itself. But this should be simple: they claim to have isolated a known compound. They should have both an exact match for the NMR spectra and LCs that are clean and match by co-injection. They could then do a chiral LC and show that only one enantiomer is in the natural product while two are in the synthetic material.

Do they have any of these things or do they simply report a rotation?

The thing I always worry about with rotations from natural sources is how pure the stuff is. Get a little bit of another material that gives a big rotation in your sample and your numbers go out the window.

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14. Hap on December 15, 2010 11:17 AM writes...

The amide looks awfully hindered, but being that it can move the proton either with base or by tautomerism (acid), and thus relieve the rotational hindrance around the amide axis, I don't know how stable any stereo there would be.

I don't need to discard the paper because the authors are Indian - bad stereo and insufficient evidence for their conclusions is enough. I vote "pathetic patent-busting exercise", if that matters.

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15. barry on December 15, 2010 11:21 AM writes...

But the NMR (in the absence of a chiral-shift reagent) should be identical to that of racemic material, and the non-equivalence of the cyclopropyl methylene hydrogens should therefore have been analysed long ago.
It's still an improbable-looking natural product.

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16. @Industry Guy on December 15, 2010 11:23 AM writes...

Dude...clicking once on "Post" is enough. Also, lay off the Indians...there's enough garbage research from the US and EU being printed in higher-impact journals than Tetrahedron!

Long shot: Excluding the carbonyl, I count 16 pi-electrons within the ring skeleton. Could the compound be twisted at the amide to avoid Huckel antiaromaticity? Sorry, I don't have access to the paper or SI?

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17. BoredChemist on December 15, 2010 11:28 AM writes...

Maybe their polarimetry cell was contaminated with garam masala ;-)

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18. petros on December 15, 2010 11:38 AM writes...

There is no mention of cochromatography with the marketed drug

Interstingly there this paper doesn;t seem to identify possible chiral forms.

Conformational analysis of nevirapine, a non-nucleoside HIV-1 reverse transcriptase inhibitor, based on quantum mechanical calculations
Journal of Computer-Aided Molecular Design
Volume 15, Number 11, 997-1004, DOI: 10.1023/A:1014881723431

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19. Nick K on December 15, 2010 1:07 PM writes...

The probability that nevapirine is also a natural product is vanishingly small.

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20. BioGuy on December 15, 2010 1:25 PM writes...

We need to have some law akin to Godwin's Law: "As the comment number approaches 20, the probability of someone making a racist or xenophobic comment approaches one".

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21. G2 on December 15, 2010 1:35 PM writes...

Why they crystallize from EtOAc and then find in the X-ray diethyl ether as the disordered solvent molecule?

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22. @21 on December 15, 2010 1:50 PM writes...

"Why they crystallize from EtOAc and then find in the X-ray diethyl ether as the disordered solvent molecule?"

Somebody cross-contaminated the solvent bottles; maybe they were too stingy to change pipettes.

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23. Will on December 15, 2010 3:07 PM writes...

Has anyone ever bothered to collect a optical rotation for the synthetic version? It would not be something that would occur to me to even bother with.

If it is a patent-busting exercise, why cloud the issue by reporting an optical rotation? that just seems to cast doubt on the structural assignment of the plant-derived material

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24. Spiro on December 15, 2010 3:20 PM writes...

There are known examples of chiral nitrogens. The compound is weird enough to fall into this category. The different chemical shifts for the cyclopropane methylene are proof of diastereotopy and suffice to convince me of the chiral nature of this compound.

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25. mod on December 15, 2010 3:38 PM writes...

I don't know how much I'm willing to trust their crystallography. The disorder in their solvent looks deeply weird, and their refinement is pretty crap considering the quality of their data (Rint = 2.2% vs R1 = 9.3%). I'm not so sure how reliable their structure is and how reliable their atom assignments are. And, as mentioned, it's in P-1 which doesn't inspire me with confidence with respect to chirality of this molcule...

(Disclaimer: I'm still pretty new to crystallography, so exercise discretion.)

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26. chiral on December 15, 2010 3:47 PM writes...

I agree to #24. This molecule is not planar, as evidenced by the X-ray structure, due to the two nitrogens in the 7-membered ring (sort of the amide rotamers). Hence, it is not superimposalbe to its mirror image, resulting in the chirality.

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27. Bingo on December 15, 2010 3:51 PM writes...

The US patents limiting FDA approval for generic nevirapine expire in Nov 2011 and the associated pediatric exclusivities expire in May 2012. That timeframe is much too short for this to be a viable attempt to circumvent the patents.

@ #4 all of the approvals you mention are tentative. Tentative approval under PEPFAR allows for sale and reimbursement outside of the US. Generics entered the Indian market as early as 2000.

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28. chris on December 15, 2010 4:00 PM writes...

These type of structures often adopt a butterfly shape and it is not impossible for them to find a single enantiomer in the crystal structure.
However I'd be really surprised to find this as a natural product.

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29. Jose on December 15, 2010 4:06 PM writes...

Cyclopropyl amino acids, yes. Alkaloids?? Only a handful... and with a pendant ring? Not so likely IMHO.

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30. processchemist on December 15, 2010 4:10 PM writes...

@27

"That timeframe is much too short for this to be a viable attempt to circumvent the patents"

Maybe you're right, but in my experience 1 year is an awful lot of time in the generic's arena.
BTW, generics entered the indian market in 2000 because of the absence of a indian patent or what?

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31. Hap on December 15, 2010 4:16 PM writes...

If it's isolable as an atropisomer, though, then the NMR of nevirapine should have shown diastereotopic cyclopropyl protons (or at least broadening of them) in previous NMR spectra. Even if it's not nonracemic, if the diastereomers are stable on the the NMR timescale (which for one of the atropisomers to be isolable, they have to be) then they ought to show the same signals. There would have to be an awful lot of people who would have to have missed something pretty obvious for this to be real.

Also, there doesn't seem to be a whole lot of isolation of any alkaloids from that species, much less something like nevirapine. Do they give reference to anything like that being found in nature, much less in their species? (The phthalate paper is a counterexample, in which something that seemed like it couldn't be natural was. However, labeling gave evidence for the phthalate being a natural product, while without the labeling, it was very hard to believe that the phthalate couldn't have come from elsewhere.)

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32. Malik on December 15, 2010 4:29 PM writes...

Thought something was fishy about this paper when I read it...

This could also be a contamination issue.. For example, Viagra type molecules are routinely identified as additives in herbal medicines. If I was referee I would be insisting on seeing an LCMS/MS of the crude and a newly collected plant

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33. Bingo on December 15, 2010 4:33 PM writes...

@ 30

"1 year is an awful lot of time in the generic's arena."

Any ANDA with a Paragraph IV certification (required if they seek approval before patent expiry) would immediately draw a lawsuit, even if the patent holder was sure it would eventually lose. The filing of the suit would trigger an automatic 30-month stay of FDA approval for the ANDA. The patents would expire before the stay.

"generics entered the indian market in 2000 because of the absence of a indian patent or what?"

Yeah, I'm not an expert on the details, but Indian patent law has changed since then, but not for older products. In any case, they don't have patent-linked approval.

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34. anon the II on December 15, 2010 4:43 PM writes...

I skimmed over the article and I'm inclined to invoke the ghost of Marcello Truzzi who almost said "Extraordinary claims require extraordinary proof."

I don't see such here.

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35. partial agonist on December 15, 2010 4:58 PM writes...

The only way I see his having room temperature atropisomers is if the structure is wrong and the C ring (as drawn) is really the regioisomer where the pyridine N is "up at the top" next to the amide and the methyl group is instead "down south" where it would have a very severe steric peri interaction with the cyclopropyl group.

I'm calling it a drylab

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36. labgloves on December 15, 2010 5:34 PM writes...

Is this really so shocking that nevirapine might be a chiral molecule?

What about all the work that has been done to show that enolates derived from 1,4-benzodiazepin-2-ones are in fact chiral and can be enantiospecifically alkylated at low temp (Carlier at VaTech, among others).

I agree that more experimentation could have been done. (Chiral HPLC etc) And, given this report, I'm quite sure that those experiments will be done . . . . I wouldn't condemn this report until those experiments are done.

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37. Anonymous on December 15, 2010 6:04 PM writes...

Call me gullible*, but rt stable atropisomers of similar rigid medium-sized rings arent all that crazy. Maybe improbable/surprising, but also well precedented.

*did not read paper

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38. Hap on December 15, 2010 6:14 PM writes...

But that's precisely why people are condemning this report - you're supposed to do that before you publish, not after. If you make claims that are inconsistent with (copious) previous experience and rather unusual in themselves, you ought to have enough evidence to explain how you came to that conclusion and how obvious alternatives were disproven.

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39. labgloves on December 15, 2010 7:04 PM writes...

To Hap,

"This sounds like some sort of lunatic patent-busting exercise, to be honest. And it sounds as if someone doesn't know what a chiral compound is."

is pretty different from:

"Should not have published this report before doing experiments x,y,z.."

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40. Hap on December 15, 2010 7:35 PM writes...

When you find an atropisomeric secondary amide, don't forget to write.

Since I suspect it'll be a while, the original tone is probably pretty well explicated.

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41. chiral on December 15, 2010 7:35 PM writes...

Though this N-cyclopropyl group looks odd in a natural product, cyclopropane is known to be part of some natural products. See the paper below:

Tetrahedron 2001, 57, 8589-8627. "Synthesis of cyclopropane containing natural products"

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42. Hap on December 15, 2010 7:53 PM writes...

Also, when you find dipyridodiazepine alkaloids, that would be a help. I found one (an antibiotic paper in 2002).

Weird structure for an alkaloid (with isolation claim) + stereo where no one has seen it (and a lot of people looked, at least at the NMR) + stable asymmetry where it is not often seen = WTF, over?

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43. Phil on December 15, 2010 7:57 PM writes...

I remember a case of a "total synthesis" which was actually a case of a desperate student buying an intermediate, then elaborating it to the natural product. Someone proved it wasn't a synthetic product based on 13C isotope distribution. Couldn't someone take a sample of their product and run the same experiment to show that it could not have some from a living source?

@41 Cyclopropanes aren't unheard of in natural products, but cyclopropylamines are another story. The point is, this molecule looks like a product of SAR, not mother nature.

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44. Fbomber on December 15, 2010 8:31 PM writes...

Atropisomers of nevirapine have been documented in a few refs.... Definitely not unprecedented in other medium rings- see telenzepine and diazepam for examples. However, the barrier to interconversion for nevirapine is way too low and so these are better described as enantiomeric conformations. This would account for the magnetically non-equivalent methylenes in the cyclopropane ring since the rate of interconversion is slow on the NMR time scale and so they will be diastereotopic. We can conclude that something is up with this paper. Can't wait to get in to work and read this one....

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45. chiral on December 15, 2010 8:33 PM writes...

We know this "cyclopropylamine" looks odd in natural products. But, this "cyclopropylamine" "core structure" does exist in natural molecules, such as (−)-allo-coronamic acid, (−)-allo-norcoronamic acid, (−)-(Z)-2,3-methanohomoserine, and (−)-(Z)-2,3-methanomethionine.

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46. gippgig on December 15, 2010 10:19 PM writes...

One plausible explanation is that the plants were growing downstream of a nevirapine manufacturer and concentrated it from the environment.

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47. provocateur on December 15, 2010 10:24 PM writes...

I do not see in any of you guys an acceptance that this might be possible after all!If they had done all the experiments then you would have questioned the purity of the material.This never ends...
I think the assertion in the paper is possible but the dataset is inadequate.The good part is it has been reproduced, the nmr's are the same and the only part remaining is the optical rotation.Frankly I would like to see some more NMR data like forming a citrate or a tartarate salt with the synthetic and natural material.More confirmation ....where are the refrees?

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48. provocateur on December 15, 2010 10:24 PM writes...

I do not see in any of you guys an acceptance that this might be possible after all!If they had done all the experiments then you would have questioned the purity of the material.This never ends...
I think the assertion in the paper is possible but the dataset is inadequate.The good part is it has been reproduced, the nmr's are the same and the only part remaining is the optical rotation.Frankly I would like to see some more NMR data like forming a citrate or a tartarate salt with the synthetic and natural material.More confirmation ....where are the referees?

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49. Yosarian on December 16, 2010 12:26 AM writes...

At c=0.0011 and A=7 the actual measurement (assuming l=1) shoud be a=0.000077. Best instrument I have worked on was able to measure a=0.001. Is all this chirality conclusion based on polarimeter noise?

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50. Yosarian on December 16, 2010 12:26 AM writes...

At c=0.0011 and A=7 the actual measurement (assuming l=1) shoud be a=0.000077. Best instrument I have worked on was able to measure a=0.001. Is all this chirality conclusion based on polarimeter noise?

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51. Iridium on December 16, 2010 3:19 AM writes...

I think that the molecule reported in fig 2 is "chiral". However, that is not really important.

You can "always" draw a conformation of a Ar1-Ar2 systems, with Ar1 different from Ar2, that "is" chiral. However free rotation makes it pointless...

What about chiral HPLC?

Probably just a salt with a chiral acid would show that the conformation adjusts to the absolute configuration fo the acid.

Bottom line....there is no enoguh evidence.

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52. processchemist on December 16, 2010 4:38 AM writes...

@Bingo

USA are not the only market in world, and there's a long legal story beetwen Boheringer and some indian subjects about nevirapine and patent prolongation tactics from the originator.

Permalink to Comment

53. provocateur on December 16, 2010 6:55 AM writes...

Derek
You were surprised that anybody could have thought this to be chiral.But the 'comments' section proves almost 3o% think it is.Now do you accuse them of not knowing what chirality is....?

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54. anon the II on December 16, 2010 8:42 AM writes...

I got tired of the mindless chatter and did some work. I used Avagadro, and nice, free molecular modeling tool to get a picture.

If you build this molecule and minimize it (MMFF94s), you find that the 6-7-6 system forms a nice curve and the cyclopropyl ring sticks out away from the curve. If you rotate the N-C bond off the cyclopropyl 180 degrees, and re-minimize, you find a nice smooth relaxation to the enantiomer. So the two enantiomers are related by a rotation of the N-C bond. I don't know the barrier to rotation. If you have Chem 3D or a real molecular modeling program (ie nothing from Tripos), you can drive that torsion with minimization and get some estimate to the barrier to rotation. The answer is that at 0 K, you can separate the enantiomers. At some higher temperature, T, you can't. Most of us believe that T is still below RT.

It is possible that if T is close to room temperature, a 50-50 mixture of chiral crystals could form from a racemate, like Pasteur's tartrate, and give rise to a chiral crystal structure. You can tell if a molecule is chiral in the crystal by the space group without knowing the absolute chirality.

The bottom line is that these guys discovered not one, but two rather amazing things and did little to dispel our suspicions of something being not quite right.

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55. processchemist on December 16, 2010 9:03 AM writes...

@54
In my old, obsolete, scientific background two specular structures convertible with a bond rotation are not a couple of enantiomers but a couple of chiral conformational isomers. A matter of words?

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56. partial agonist on December 16, 2010 10:26 AM writes...

provocateur,

The key here is that the enantiomers are purportedly stable/persistent and are not interconverting at room temperature. Most of us agree that at very low temperatures the compound could exist in enantiomeric conformations (discreet atropisomers)

I see no precedence, though, for a sufficiently high barrier to N inversion to allow ROOM TEMPERATURE atropisomerism in this case. When such high barriers exist, to my knowledge there are substantial steric repulsions responsible. In this case the interactions creating such a barrier would be an amide NH (tiny) with a neighboring methyl, or the cyclopropyl with neighboring lone pairs on the two pyridine nitrogens (very tiny).

A computational chemist can calculate the barriers quite well, I would think, since this structure would be relatively rigid. Such a computation, along with a variable temperature coalescence experiment, should be CENTRAL to this paper and is not.

The obvious point as well is that the reading public should not be obligated to test any authors fastastic claims that lack compelling evidence. Those fantastic claims should be tested up front by the author, who in this case doesn't even seem to realize the remarkable nature of those claims.

Permalink to Comment

57. anon the II on December 16, 2010 10:53 AM writes...

@55

I would compare them to the chiral binaphthyl systems that abound in the literature. It is not a matter of words but a matter of temperature. At low enough temperature, I believe my words are used correctly.

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58. JAB on December 16, 2010 11:15 AM writes...

No way this is a natural product. But 3.5 gms of it? Sounds like someone snuck into the lab and dumped nevirapine into their extract. But why would they even want to chase this spot on TLC? I would go for a chiral impurity causing the single digit rotation. Tetrahedron editors should be ashamed of their lack of stringency of review.

Permalink to Comment

59. Phil on December 16, 2010 11:20 AM writes...

anon the II:

Binapthyl is conformationally stable up to something like 150 °C (couldn't find the data in the minute I looked). Amines are conformationally stable at something like -100 °C. Technically, every amine is chiral by your definition. But practically, we don't treat amines as chiral, except in extraordinary cases (for instance, when they bear exceptionally strong withdrawing groups).

Many molecules adopt rigid conformations at low temperature (and also in the solid phase, which is why the crystal structure doesn't mean much), but we still have to think about them as freely rotating or we miss a great deal of the inherent reactivity.

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60. Hap on December 16, 2010 11:23 AM writes...

Binaphthyl systems have a tetrasubstitued core bond with peri-substituents that make rotation hindered enough to isolate and keep enantiomers. The amide H means that the nitrogen is far less hindered and can also be removed/isomerized by base or by acid routes (via tautomerization). That should make this stereo significantly less stable that that of binap systems. You can get hindered amide atropisomers (Curran, for example), but they are generally tetrasubstituted (N with carbonyl and tert-butyl, aryl with at least one ortho-substituent and probably two).

It is a matter of convention, but generally atropisomers should have an interconversion half-life of > 1000s (16-17 min) at ambient temperature (298 K, roughly). This seems unlikely to fit that definition. While the difference between conformational isomers and atropisomers is a matter of convention, we don't generally talk about chair isomers of substituted cyclohexanes, though they have separate existences at low T (160 K).

Permalink to Comment

61. Hap on December 16, 2010 11:26 AM writes...

Binaphthyl systems have a tetrasubstitued core bond with peri-substituents that make rotation hindered enough to isolate and keep enantiomers. The amide H means that the nitrogen is far less hindered and can also be removed/isomerized by base or by acid routes (via tautomerization). That should make this stereo significantly less stable that that of binap systems. You can get hindered amide atropisomers (Curran, for example), but they are generally tetrasubstituted (N with carbonyl and tert-butyl, aryl with at least one ortho-substituent and probably two).

It is a matter of convention, but generally atropisomers should have an interconversion half-life of > 1000s (16-17 min) at ambient temperature (298 K, roughly). This seems unlikely to fit that definition. While the difference between conformational isomers and atropisomers is a matter of convention, we don't generally talk about chair isomers of substituted cyclohexanes, though they have separate existences at low T (160 K).

Permalink to Comment

62. anon the II on December 16, 2010 2:57 PM writes...

Hi Hap and Phil,

The interconversion between enantiomers relies on the rotation of the bond between the N of the 7-membered ring and the carbon of the cycylopropane. All of the nitrogens are sp2 and interconversion is not dependent on the energy of nitrogen inversion or amide rotation. It requires passing the cyclopropyl hydrogens past the pyridine lone pair. However, I believe that this is facile at RT and agree with you that this ain't no chiral molecule. But at the same time, it's important to recognize where the barrier comes from. Everyone seems to be missing that.

And, yes, the editors blew it big time.

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63. Hap on December 16, 2010 3:28 PM writes...

I guess I couldn't see how that N could be chiral. At least in the crystal structure (Excimer's reference), that N isn't flat, so it can't really be sp2 (the diazepine ring is curved, and since neither the amide or the pyridines can really accommodate a curvature, the nonplanarity has to be at the N. (If the N were sp2, the middle ring would be antiaromatic, as well.) Inversion of the lone pair (which inverts the curvature of the diazepine) or rotation of the cyclopropyl group (either of which should be a really low energy transition) would interconvert the diastereotopic cyclopropyl protons. Are there example of hindered rotation because of flanking lone pairs?

The amide I could sort of see generating atropisomers (but not really), but the ring N, I can't see at all. They should have shown diastereotopic cyclopropyl protons, which somebody before now had to notice.

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64. Rock on December 16, 2010 7:49 PM writes...

Yosarian in comment #50 is spot on.
With 3.5 g to work with, why would anyone in their right mind get a rotation using one thousandth the typically used concentration?

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65. Fbomber on December 16, 2010 8:44 PM writes...

It's gippgig (46) that's nailed it on the head. Nevirapine from dandelion seeds? Gimme a break....... And nevirapine is not conformationally stable at rt.

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66. featherson on December 19, 2010 9:34 PM writes...

I agree with process chemist #5-end of story-nothing to with racism-just pragmatism and truth-c'mon fredo it's not personal, it's business...

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67. featherson on December 19, 2010 9:44 PM writes...

Excuse me I meant I agree with #9 Industry Guy-other comments remain the same

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68. china law firm on December 20, 2010 3:42 AM writes...

I agree with process chemist #5-end of story-nothing to with racism-just pragmatism and truth-c'mon fredo it's not personal, it's business...

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69. Take on December 25, 2010 11:18 PM writes...

The cif file in the supplementary information shows completely planer structure. You can see it using x-ray structure viewer (such as Mercury).

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70. dave on January 5, 2011 3:57 PM writes...

@69: The "cif" file is actually just an automatically generated "mol" file, which is a glorified chem3D representation - it is NOT the crystal structure.

I tried to find their cif, but was unable to (no mention of a CCDC deposition, and no SI, good old Tetrahedron), but I did check one of their references regarding crystal structures of the SYNTHETIC compound. One of them (the ethyl acetate solvate to be exact) is virtually identical to the crystal data reported in the Tetrahedron paper: same unit cell, same space group, same Z value. All of the structures from this second paper contain CENTROSYMMETRIC DIMERS of Nevirapine. This means that both of the atropisomers/enantiomers/conformers exist in the crystal. They couldn't possibly have generated a real optical rotation with something that crystallizes in P-1!!

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71. colin calabrese on January 6, 2011 2:16 PM writes...

Although I'm suspicious of their chirality claims, I'm SURE nevirapine is not a natural product.

Reminds me of several papers that claimed benzodiazepines such diazepam, lorazepam and nordazepam were being produced in plants. BZDs are simply very persistent, stable compounds that are probably contaminating the environment at a very low level. Thousands of kg of benzodiazepines are produced annually, and given their lipophilic and inert nature I'm not surprised they are turning up in supposedly "endogenous" roles.

I think the same thing is happening here with nevirapine.

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72. Norepi on January 6, 2011 4:51 PM writes...

Chirality geek here. N-C bonds (aryls too) can definitely possess axial chirality if there's enough gorp stacked around the rotation site - some really nice axially chiral natural products (bis-pyrroles and things) were isolated about four years back (I think it was Fenical at UCSD). The things were conformationally stable at RT but can be racemized in refluxing toluene. In order for something to possess actual atropisomers at room temp, the barrier to rotation must be >12 kcal/mol (give or take 1.5 either way). Anybody along the chain here (author, referree, editor) could have put this thing into MacroModel, performed a 1-2˚ step dihedral rotation (as #54 says), and obtain the actual rotational barrier. I can guarantee that it's not going to be 12 kcal/mol. Lousy all around.

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73. Jonathan Clayden on June 24, 2011 9:10 AM writes...

If anyone is still reading this thread, we've now finished a dynamic NMR and DFT study on the butterfly-like inversion of nevirapine. And both agree the barrier is.... 70-80 kJ mol-1 at 25 C. That's a half life of seconds max. Nevirapine is not atropisomeric at room temp. But it would be at about -30 C (depending on delta S dagger) The original paper is withdrawn I know, but some of the confusion in this string of posts makes it clear that this data needs to be in the public domain - it will be published shortly. But to all those who have posted their firm convictions about Nevirapine's possible chirality, one way or the other, please note that (1) the cyclopropyl group of Nevirapine is indeed an AA'BB'X system (ie all 4 CH's are diastereotopic, so racemisation is slow at RT on the NMR timescale) and (2) take a look at J. Org. Chem. (2011), 76(12), 5123-5131.

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